PROJECT SUMMARY Spiral ganglion neurons (SGNs) and auditory nerve fibers are the primary carriers of sound information from the cochlea to the brain. About 95% of auditory nerve fibers and SGN somas are myelinated by Schwann cells and satellite cells, respectively. The integrity of myelin and the glial-associated paranodal structures at the node of Ranvier are critical for normal auditory nerve function and axonal survival in the central nervous system. However, little is known about how cochlear injury affects the activity of myelinating glial cells and how alterations in myelin and paranodal structure contribute to auditory nerve degeneration and sensorineural hearing loss (SNHL). The aims of this project will address these questions by examining pathophysiological alterations of glial cells and the underlying molecular mechanisms associated with auditory nerve degeneration following exposure to noise or loss of sensory hair cells. Quaking (QKI) RNA binding proteins are key regulators of myelination and are required for the maintenance of paranodal integrity in other regions of the brain. Our preliminary studies have shown that 1) QKI proteins are expressed in Schwann and satellite cells in both mouse and human auditory nerve, and 2) unique expression patterns of QKI isoform transcripts are present in the auditory nerve of the developing cochlea and in the adult cochlea exposed to noise. We have also shown that specific deletion of QKI expression in Schwann cells results in deterioration of paranodal structures, loss of myelin, and axon degeneration in the auditory nerve. Based on these new findings, we hypothesize that regulation of QKI RNA binding proteins in glial cells controls the formation, maintenance and repair of the myelin sheath and node of Ranvier in the auditory nerve. The proposed experiments will be conducted to 1) establish the regulatory roles of the QKI RNA binding proteins in formation and maintenance of the myelin sheath and paranodal structures in the postnatal (Aim 1) and adult (Aim 2) auditory nerve; and 2) determine how dysregulation of QKI protein expression leads to downstream changes that result in demyelination, disruption of nodes of Ranvier and auditory nerve degeneration following exposure to noise or after sensory hair cell loss (Aim 3). Successful completion of these aims will generate new knowledge on the vital roles of myelinating glia cells in normal auditory function and how aberrant functioning of glial cell- associated RNA binding proteins and post-transcriptional gene regulation contributes to auditory nerve degeneration. These findings will support necessary translational research evaluating the therapeutic potential of RNA binding proteins and their targets to ameliorate SNHL and other neurodegenerative disorders.